New selenium-based safety-catch linkers: Solid-phase semisynthesis of vancomycin

Article abstract of DOI:10.1002/(SICI)1521-3773(20000317)39:6<1084::AID-ANIE1084>3.0.CO;2-O

Pro-allyl and pro-alloc linkers can be formed by alkylation or esterification of a selenium-bound resin (the example shown is for the formation of a polymer-bound pro-allyl derivative) and can be readily cleaved in excellent yields under mild conditions. The scope of the pro-allyl linker has been demonstrated with the solid-phase semisynthesis of vancomycin. Alloc = allyloxycarbonyl.

Full text of DOI:10.1002/(SICI)1521-3773(20000317)39:6<1084::AID-ANIE1084>3.0.CO;2-O

COMMUNICATIONS
[1] a) M. L. Zapp, S. Stern, M. R. Green, Cell 1993, 74, 969 ± 978; b) B.
Clouet-dꢁOrval, T. K. Stage, O. C. Uhlenbeck, Biochemistry 1995, 34,
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5, R277-R283; d) U. von Ahsen, J. Davies, R. Schroeder, Nature 1991,
353, 368 ± 370; e) Y. Wang, J. Killian, K. Hamasaki, R. Rando,
Biochemistry 1996, 35, 12338 ± 12346; f) L. Jiang, A. K. Suri, R. Fiala,
D. J. Patel, Chem. Biol. 1997, 4, 35 ± 50.
New Selenium-Based Safety-Catch Linkers:
Solid-Phase Semisynthesis of Vancomycin**
K. C. Nicolaou,* Nicolas Winssinger, Robert Hughes,
Christopher Smethurst, and Suk Young Cho
[2] a) D. Moazed, H. F. Noller, Nature 1987, 327, 389 ± 394; b) P.
Purohit, S. Stern, Nature 1994, 370, 659 ± 662; c) D. Formy,
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1371.
[3] a) M. Howard, R. A. Frizzell, D. M. Bedwell, Nat. Med. 1996,
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550 ± 555.
[5] A. B. Raitano, Y. E. Whang, C. L. Sawyer, Biochem. Biophys. Acta
1997, F201-F216.
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Weichselbaum, D. W. Kufe, Nature 1995, 376, 785 ± 788; b) Z. G. Liu,
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Wang, Nature 1996, 384, 273 ± 276.
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13164 ± 13169.
The generation of molecular diversity through solid-phase
combinatorial chemistry has become an important component
of the drug discovery process.[1] An enduring challenge in the
design of solid-phase synthetic sequences is the selection of an
appropriate linker[2] that is stable to the proposed chemistry,
yet which can be readily and practically cleaved. Solid-phase
synthesis of natural products offers a particularly good
platform to evaluate linkers because of the multitude of
functionality often present. Vancomycin[3] (1, Scheme 1),
renowned for its activity against methicillin-resistant Staph-
ylococcus aurus (MRSA), has been used for the past forty
years to treat Gram-positive bacterial infections. The emer-
gence of vancomycin-resistant enterococci strains (VRE) has
raised serious health concerns and prompted a renewed vigor
in the field of glycopetide antibiotics.[3, 4] Researchers from Eli
Lilly have demonstrated that modification of the oligosac-
charide portion of vancomycin can enhance its activity against
VRE to a clinically significant level.[5] However, more in-
depth investigations of the role of the oligosaccharide unit in
the glycopeptideꢁs biological activity has been hampered by
the synthetic inaccessibility of analogues. The completion of
the total synthesis of vancomycin in these laboratories[6]
encouraged us to investigate a solid-phase approach to the
glycosidation of vancomycinꢁs aglycon, which might be
applicable to the semisynthesis of vancomycin libraries for
biological screening purposes. Herein we report the prepara-
tion and scope of a selenium-based safety-catch linker and its
application to the solid-phase semisynthesis of vancomycin
(1).
[11] M. Hendrix, E. S. Priestly, G. F. Joyce, C.-H. Wong, J. Am. Chem. Soc.
1997, 119, 3641 ± 3648.
[12] M. Hendrix, P. B. Alper, E. S. Priestly, C.-H. Wong, Angew. Chem.
1997, 109, 119 ± 122; Angew. Chem. Int. Ed. Engl. 1997, 36,
95 ± 98.
[13] W. A. Greenberg, E. S. Priestly, P. S. Sears, P. B. Alper, C. Rosenbohm,
M. Hendrix, S.-C. Hung, C.-H. Wong, J. Am. Chem. Soc. 1999, 121,
6527 ± 6541.
Vancomycinꢁs carboxylic acid group was identified as the
most suitable site for linkage to a solid support since it is the
only singularly present functional group on vancomycin and,
therefore, does not require some form of regioselective
derivatization. The required protected vancomycin 2 was
readily prepared in two steps from 1 as shown in Scheme 1.
The criteria for the selection of a linker included acid and base
[*] Prof. K. C. Nicolaou, N. Winssinger, R. Hughes, Dr. C. Smethurst,
Dr. S. Y. Cho
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡ 1)858-784-2469
and
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
E-mail: kcn@scripps.edu
[**] We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic
and mass spectrometric assistance, respectively. This work was
financially supported by the National Institutes of Health (USA),
The Skaggs Institute for Chemical Biology, a fellowship from the
George Hewitt Foundation (N. W.), and grants from Schering Plough,
Pfizer, Glaxo, Merck, Hoffmann-La Roche, DuPont, and Abbott
Laboratories.
1084
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0570-0833/00/3906-1084 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 6

COMMUNICATIONS
OTBS
OTBS
TBSO
CbzHN
TBSO
TBSO
CbzHN
TBSO
OTBS
OTBS
O
O
O
O
O
O
O
O
O
O
Cl
Cl
linker
O
O
O
O
OTBS
O
OTBS
O
see insert
TBSO
TBSO
Cl
Cl
Cbz
Cbz
H
H
O
O
H
H
H
N
H
N
NMe
NMe
N
N
N
N
g) [Pd(PPh3)4] (cat.), nBuSnH
(>90%)
N
H
N
H
N
N
H
H
H
H
O
O
O
O
O
O
H
H
O
O
X
NH
O
NH
O
Y
HO
O
NH2
NH2
OTBS
OTBS
OTBS
OTBS
3
O
TBSO
TBSO
2 =
HO
protected
vancomycin
a) TBSOTf, 2,6-lut.
b) Cbz-Cl, NaHCO3
O
OH
O
5
O
(52% for two steps)
c) DEAD, Ph3P
(66%)
HO
protected
O
O
protected
vancomycin
vancomycin
2
3a
OH
HO
HO
H2N
f) allylBr,
CsCO3
OH
(97%)
O
O
6
O
O
O
O
4
O
d) [(Cy3P)2Cl2RuCHPh]
(60%)
O
Cl
O
protected
vancomycin
O
protected
O
O
vancomycin
3b
3c
OH
HO
Cl
H
O
O
H
N
O
H
H
NMe
N
O
N
N
N
H
H
H
O
O
H
O
N
H
OMs
O
O
O
7
O
NH
O
N
O
HO
protected
vancomycin
e) NaHCO3
(72%)
protected
vancomycin
HO
H
NH2
1: vancomycin
OH
OH
2
HO
Scheme 1. Protection of vancomycin, as well as loading onto and cleavage from allyl ester resins. Reagents and conditions: a) TBSOTf (excess), 2,6-lutidine
(120 equiv), CH2Cl2:DMF (10:1), 238C, sonication, 8 h; b) CbzCl (5.0 equiv), NaHCO3 (10 equiv), 1,4-dioxane: H2O (3:1), 238C, 3 h, 52% over two steps;
c) 5 (7.0 equiv), DEAD (7.0 equiv), Ph3P (7.0 equiv), THF, 158C, 1.5 h, 66%; d) 6 (10.0 equiv), [(Cy3P)2Cl2RuCHPh], (2 Â 0.1 equiv), benzene, 658C, 15 h,
60%; e) 7 (4.0 equiv), NaHCO3 (10.0 equiv), 4-Š molecular sieves, 238C (vacuum), 0.5 h; DMF, 658C, 18 h, 72%, f) allylBr (10.0 equiv), NaHCO3
(10.0 equiv), 4-Š molecular sieves, DMF, 238C (vacuum), 0.5 h; 8 h, 97%. Cbz ˆ benzyloxycarbonyl, Cy ˆ cyclohexyl, DEAD ˆ diethyl azodicarboxylate,
DMF ˆ N,N-dimethylformamide, lut. ˆ lutidine, TBS ˆ tert-butyldimethylsilyl.
stability, as well as mild loading and cleavage conditions
compatible with silyl protecting groups. Our first efforts
focused on photolabile[7] linkers because of their mild
cleavage; however, an acceptable compromise between load-
ing and cleavage efficiency could not be reached. We then
turned our attention to allylic ester linkers.[8] As shown in
Scheme 1, protected vancomycin 2 was loaded in good yield
using Mitsunobu, cross metathesis, or alkylation techniques.
All three linkers were cleaved in excellent yield under the
very mild palladium(0)-mediated allyl transfer conditions.[9]
However, the cleavage efficiency of the linkers in 3a and 3b
was dramatically reduced after exposure to the Lewis acidic
conditions utilized in the glycosidation, presumably as a result
of a [3,3] sigmatropic rearrangement[10] to give a secondary
allylic ester. The allylic acrylate linker in 3c, although stable
to the glycosidation conditions, was found to be susceptible to
premature cleavage and deactivation, which was assumed to
arise from a nucleophilic attack on the acrylate functionality.
It soon became clear that despite the attractiveness of their
mild and efficient cleavage, the linkers in 3a ± c were not
suitable for application to the vancomycin problem.
In the search for alternative strategies to solve the problem
at hand we turned our attention to our recently reported
preparation of polymer-bound selenenyl bromide.[11] We
reasoned that the facile oxidation/elimination of the poly-
mer-bound phenylseleno group could be used to mask an
allylic functionality (Figure 1), thus serving as a pro-allyl
safety-catch linker. Since the presence of residual tin can be
detrimental to purification and biological assays we further
envisioned the use of polymer-bound tin hydride[12] for the
removal of the allyl group. Thus, the proposed strategy retains
the critical, but cumbersome elements on the resin, and
provides a measure of waste control and disposal. To test the
scope of this proposal, we prepared resins 9 ± 11 (Scheme 2).
Thus, LiBH4 reduction of the polymer-bound phenyl selenen-
yl bromide 8 afforded the corresponding lithiated selenium
species, which was quenched with either 1,3-diiodopropane or
3-iodopropanol to furnish resins 9 or 10, respectively. Treat-
Angew. Chem. Int. Ed. 2000, 39, No. 6
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1085

COMMUNICATIONS
O
a) 9, CsCO3 or 10, DCC
O
O
Se
X
O
H2O2
II
(x = I or OH)
R1
OH
O
O
R1
b) 1. H2O2 (86% from 9)
2. VI, [Pd(PPh3)4] (cat.)
Se
Se
12
O
R
Se
13
15
17
III
(96%)
O
I
O
c) 11, Et3N, 4-DMAP
R2
R2 OH
14
O
HO
R
Se
O
O
R
+
-
nBu nBu
b) 1. H2O2 (78% from 10)
2. VI, [Pd(PPh3)4] (cat.)
H
H
Sn
H
(97%)
VI
IV
[1,2-syn elimination]
O
d) 11, Et3N, 4-DMAP
R3
O
R3 NH2
16
O
N
H
[Pd(PPh3)4] (cat.)
Se
e) 1. H2O2 (82% from 10)
2. VI, [Pd(PPh3)4] (cat.)
O
R
V
(93%)
Figure 1. General concept of the selenium-based resin as a pro-allyl or pro-
alloc safety-catch linker.
Scheme 3. Loading onto and cleavage from pro-allyl and pro-alloc
selenium resins. Reagents and conditions: a) 12 (4.0 equiv), CsCO3
(4.0 equiv), DMF, 508C, 5 h or 12 (4.0 equiv), DCC (4.0 equiv), DMF,
238C, 15 h; b) 1. H2O2 (2.0 equiv), THF, 238C, 2 h; Me2S (4.0 equiv), 608C,
10 h, 86% from 9 and 78% from 10; 2. VI (3.0 equiv), [Pd(PPh3)4]
(0.1 equiv), CH2Cl2, 238C, 0.5 h, 96% for 12 and 97% for 14; c) 11
(4.0 equiv), Et3N (5.0 equiv), 4-DMAP (0.1 equiv), 238C, 6 h; d) 11
(4.0 equiv), Et3N (5.0 equiv), 4-DMAP (0.1 equiv), 238C, 3 h; e) 1. H2O2
(2.0 equiv), THF, 238C, 2 h; Me2S (4.0 equiv), 608C, 10 h, 82% from 10;
2. VI (3.0 equiv), [Pd(PPh3)4] (0.1 equiv), AcOH (4.0 equiv), CH2Cl2, 238C,
0.5 h, 93%. R1 ˆ 4-bromophenyl, R2 ˆ 4-iodobenzyl, R3NH2 ˆ methoxyva-
line, DCC ˆ N,N'-dicyclohexylcarbodiimide, 4-DMAP ˆ 4-dimethylamino-
pyridine.
a) LiBH4;
I
Se
I
I
9
(92%)
b) LiBH4;
OH
Se
Se Br
10
I
OH
(94%)
c) COCl2
O
O
Cl
Se
SeBr
11
8
furnished carboxylic acid 12, alcohol 14, and amine 16 in
yields of 86, 78, and 82%, respectively. More importantly,
loading and cleavage of protected vancomycin derivative 2
proceeded smoothly via intermediate 18 (Scheme 4) and
without the previously discussed limitations of the allyl linkers
shown in Scheme 1.
Scheme 2. Synthesis of pro-allyl and pro-alloc selenium linkers. Reagents
and conditions: a) LiBH4 (1.5 equiv), THF, 08C, 0.5 h, wash, 1,3-diiodo-
propane (4.0 equiv), THF:DMF (1:1), 238C, 5 h, 92%; b) LiBH4
(1.5 equiv), THF, 08C, 0.5 h, wash, 3-iodopropanol (4.0 equiv), THF:DMF
(1:1), 238C, 5 h, 94%; c) COCl2 (4.0 equiv), THF, 238C, 5 h. Yields are
calculated on the basis of the mass gain of the polymer. Alloc ˆ allyloxy-
carbonyl.
The now readily available polymer-bound vancomycin
derivative 2 was utilized to demonstrate an efficient sequence
of deglycosidation and re-glycosidation reactions leading to
vancomycin (1, Scheme 5). Thus, the disaccharide moiety was
hydrolyzed from 2 under acidic conditions to provide
polymer-bound phenol 19, which was glycosylated with the
imidate 20[6a] (BF3 ´ Et2O) to afford glycoside 21. Deprotection
of the C-2 alloc group using palladium(0)-mediated allyl
transfer conditions afforded compound 22 (see Table 1) in
excellent yield. The polymer-bound monosaccharide 22 was
then subjected to a second glycosidation reaction with
ment of resin 10 with phosgene afforded polymer-bound
chloroformate 11. We were gratified to find that the pro-allyl
ester 13 (Scheme 3) was formed smoothly by either alkylation
or esterification of resins 9 and 10, respectively. Furthermore,
formation of pro-alloc derivatives 15 and 17 also proceeded
smoothly (Scheme 3). Treatment of polymer-bound pro-allyl
derivative 13 as well as pro-alloc compounds 15 and 17 with
H2O2, followed by exposure to catalytic amounts of
[Pd(PPh3)4] and polymer-bound tin hydride VI (Figure 1)
OTBS
OTBS
TBSO
CbzHN
TBSO
TBSO
CbzHN
TBSO
OTBS
OTBS
O
O
9
I
Se
O
O
O
O
O
O
a) CsHCO3, 4 Å MS,
(86%)
O
O
Cl
Cl
O
O
O
O
OTBS
O
OTBS
O
TBSO
TBSO
Cl
Cl
Cbz
Cbz
H
O
H
O
H
H
H
N
H
N
(82%)
b) 1. H2O2
2. [Pd(PPh3)4]
NMe
N
NMe
N
N
N
N
H
N
H
N
N
H
H
nBu3SnH (94%)
H
H
O
O
O
O
O
O
H
H
O
O
NH
O
NH
O
O
HO
Se
NH2
NH2
OTBS
OTBS
2
18
OTBS
OTBS
TBSO
TBSO
Scheme 4. Loading and cleavage of the vancomycin scaffold using a pro-allyl safety-catch linker. Reagents and conditions: a) 9 (8.0 equiv), CsHCO3
(5.0 equiv), DMF, 238C (vacuum), 0.5 h, 508C, 5 h, 86%; b) 1. H2O2 (2.0 equiv), THF, 238C, 2 h; Me2S (4.0 equiv), 238C, 48 h, 82%; 2. [Pd(PPh3)4]
(0.1 equiv), nBuSn3H (4.0 equiv), CH2Cl2, 0.5 h, 94%. The loading yield is based on the mass gain of the polymer.
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Angew. Chem. Int. Ed. 2000, 39, No. 6

COMMUNICATIONS
OTBS
TBSO
CbzHN
TBSO
OTBS
O
O
O
O
OH
Cl
O
O
Cl
O
O
O
OTBS
Cbz
TBSO
Cl
a) TFA:Me2S:CH2Cl2
(1:1:1)
OTBS
O
TBSO
Cl
O
O
O
H
H
H
Cbz
NMe
N
N
H
O
H
N
H
N
N
NMe
N
N
N
H
H
N
H
N
H
O
O
O
H
O
(>95%)
H
H
O
O
O
H
O
NH
O
NH
O
O
NH2
Se
O
NH2
OTBS
OTBS
Se
OTBS
OTBS
19
TBSO
18
TBSO
b) BF3•Et2O
(>90%)
O
OC(NH)CCl3
OAlloc
AcO
OAc
AcO
OAc
AcO
OAc
OTBS
AcO
20
OTBS
O
HO
O
AllocO
O
Cl
O
O
O
Cl
c) [Pd(PPh3)4] (cat.),
nBu3SnH
OTBS
O
O
O
TBSO
Cl
Cbz
O
O
H
H
H
OTBS
O
TBSO
Cl
NMe
N
N
N
Cbz
N
H
N
(>95%)
O
O
H
N
H
H
H
H
NMe
O
O
N
H
O
O
N
N
H
N
NH
O
H
H
O
O
O
H
O
NH
O
O
NH2
Se
OTBS
OTBS
O
NH2
22
Se
TBSO
OTBS
OTBS
21
d) BF3•Et2O
(>85%)
TBSO
Me
AcO
O
F
OAc
AcO
CbzHN
AcO
OAc
O
OTBS
Me NHCbz
23
AcO
CbzHN
AcO
O
OTBS
O
O
O
O
O
O
Cl
O
O
Cl
OTBS
O
O
O
TBSO
Cl
Cbz
O
O
H
H
H
OTBS
TBSO
Cl
NMe
N
N
N
Cbz
N
H
N
e) H2O2
(80%)
O
O
H
O
H
H
H
H
NMe
N
O
O
N
O
H
O
N
N
N
NH
O
H
H
H
O
O
H
O
O
NH
O
O
NH2
OTBS
OTBS
O
NH2
25
Se
TBSO
OTBS
OTBS
f) K2CO3, MeOH (86%)
g) CsF (62%)
24
TBSO
OH
O
OH
HO
CbzHN
HO
HO
H2N
HO
OH
OH
O
O
O
O
O
O
O
Cl
Cl
O
O
O
O
O
h) [Pd(PPh3)4],
OH
OH
HO
nBu3SnH (95%)
Cl
HO
Cl
Cbz
H
O
O
i) Pd/C, NH4HCO2 (81%)
O
H
O
H
H
H
N
O
H
H
NMe
N
N
N
NMe
N
N
N
N
H
N
N
H
H
H
H
H
O
O
H
O
O
O
H
O
O
NH
O
O
NH
O
O
HO
NH2
NH2
1: vancomycin
OH
OH
OH
OH
26
HO
HO
Scheme 5. Solid-phase semisynthesis of vancomycin 1. Reagents and conditions. a) TFA:Me2S:CH2Cl2 (1:1:1), 238C, 3 h, >95%; b) 20 (6.0 equiv), BF3 ´
Et2O (9.0 equiv), 4-Š molecular sieves, 40 !08C, 12 h, >90%; c) [Pd(PPh3)4] (0.1 equiv), nBu3SnH (10.0 equiv), CH2Cl2, 238C, 2 h, >95%; d) 23
(4.0 equiv), BF3 ´ Et2O (6.0 equiv), 40 !08C, 4 h, >85%; e) H2O2, THF, 238C, 48 h, 80%; f) K2CO3, MeOH, 238C, 6 h, 86%; g) CsF, DMF, 238C, 15 h,
62%; h) [Pd(PPh3)4], nBu3SnH, DMF, 238C, 1 h, 95%; i) 10% Pd/C, NH4HCO2, H2O:AcOH (1:1), 238C, 4 h, 81%. Ac ˆ acetyl, TFA ˆ trifluoroacetic acid.
1
Yields for the reactions carried out on a solid phase are estimates based on H NMR, MS, and TLC analysis of the crude cleavage product.
Angew. Chem. Int. Ed. 2000, 39, No. 6
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1087

COMMUNICATIONS
Table 1. Selected physical data for compounds 22 and 25.
[3] For reviews, see a) K. C. Nicolaou, C. N. C. Boddy, S. Bräse, N.
Winssinger, Angew. Chem. 1999, 111, 2230± 2287; Angew. Chem. Int.
Ed. 1999, 38, 2097 ± 2152; b) D. H. Williams, B. Bardsley, Angew. Chem.
1999, 111, 1264± 1286; Angew. Chem. Int. Ed. 1999, 38, 1172 ± 1193.
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22 (oxidative cleavage product): Rf ˆ 0.39 (silica gel, 5% MeOH in
CH2Cl2); 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.53 ± 7.48 (m, 2H),
7.43 ± 7.38 (m, 2H), 7.38 ± 7.27 (m, 7H), 7.27 (s, 1H), 7.08 (d, J ˆ 2.0 Hz,
1H), 7.01 (dd, J ˆ 9.5, 2.0 Hz, 1H), 6.78 (d, J ˆ 8.0 Hz, 1H), 6.41 (d, J ˆ
1.5 Hz, 1H), 6.39 (d, J ˆ 1.5 Hz, 1H), 5.98 ± 5.90 (m, 1H), 5.90 ± 5.87 (m,
1H), 5.79 (s, 1H), 5.56 ± 5.17 (m, 9H), 5.01 ± 4.84 (m, 6H), 4.73 ± 4.50 (m,
6H), 4.25 ± 4.18 (m, 1H), 4.11 (s, 1H), 3.89 ± 3.84 (m, 1H), 3.74 ± 3.68 (m,
1H), 3.78 ± 3.70 (m, 1H), 3.60 (dd, J ˆ 11.0, 3.2 Hz, 1H), 2.93 (s, 3H,
NCH3), 2.55 ± 2.40 (m, 2H), 2.03 (s, 3H, COCH3), 2.00 (s, 3H, COCH3),
1.78 ± 1.75 (m, 1H), 1.53 ± 1.49 (m, 2H), 1.01 (s, 9H, tBuSi), 0.94 (s, 9H,
tBuSi), 0.93 ± 0.91 (m, 6H), 0.89 (s, 9H, tBuSi), 0.77(s, 9H, tBuSi), 0.73 (s,
9H, tBuSi), 0.63 (s, 9H, tBuSi), 0.23 (s, 6H, CH3Si), 0.18 (s, 3H, CH3Si),
0.12 (s, 3H, CH3Si), 0.10 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.09 (s, 3H,
CH3Si), 0.08 (s, 3H, CH3Si), 0.04 (s, 3H, CH3Si), 0.03 (s, 3H, CH3Si), 0.08
‡
(s, 3H, CH3Si), 0.09 (s, 3H, CH3Si); MS (ES ): calcd for C110H160Cl2N8O26-
‡
Si6 [M‡H ]: 2247; found: 2247.
25: Rf ˆ 0.40 (silica gel, 5% MeOH in CH2Cl2); 1H NMR (600 MHz,
CD3OD, 330 K): d ˆ 7.65 ± 7.45 (m, 3H), 7.40 ± 7.20 (m, 12H), 7.10 ± 7.08
(m, 2H), 7.03 (m, 2H), 6.80 (d, J ˆ 0.5 Hz, 1H), 6.78 (d, J ˆ 0.5 Hz, 1H),
6.44 (d, J ˆ 2.0 Hz, 1H), 6.40 (s, 1H), 5.91 (m, 1H), 5.83 ± 5.78 (m, 2H),
5.64 ± 5.45 (m, 2H), 5.44 ± 5.28 (m, 5H), 5.26 ± 5.10 (m, 5H), 5.01 and 4.88
(AB, J ˆ 12.5 Hz, 2H), 4.64 (m, 2H), 4.18 ± 4.07 (m, 2H), 3.85 ± 3.80 (m,
2H), 3.64 (m, 1H), 2.94 (s, 3H, NCH3), 2.48 (m, 2H), 2.03 (s, 3H), 2.05 ±
1.98 (m, 5H), 1.92 (s, 3H), 1.55 (brs, 3H), 1.29 (s, 3H), 1.09 (m, 3H), 1.02 (s,
9H, tBuSi), 0.97 (s, 9H, tBuSi), 0.93 (m, 6H), 0.88 (s, 9H, tBuSi), 0.82 (s,
9H, tBuSi), 0.79 (s, 9H, tBuSi), 0.71 (s, 9H, tBuSi), 0.24 (s, 3H, CH3Si), 0.23
(s, 3H, CH3Si), 0.19 (s, 3H, CH3Si), 0.18 (s, 3H, CH3Si), 0.13 (s, 3H, CH3Si),
0.12 (s, 3H, CH3Si), 0.10 (m, 6H, CH3Si), 0.04 (s, 3H, CH3Si), 0.03 (s, 3H,
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‡
CH3Si), 0.06 (s, 3H, CH3Si), 0.08 (s, 3H, CH3Si); MS (ES ): calcd for
‡
C127H181Cl2N9O31Si6Na [M‡Na ]: 2592; found: 2592.
glycosyl fluoride 23[6a] (BF3 ´ Et2O) to deliver fully protected
polymer-bound vancomycin derivative 24, which was cleaved
with H2O2 to release allyl derivative 25 (see Table 1). Finally,
vancomycin (1) was obtained from 26 through a deprotection
sequence involving deacetylation (K2CO3/MeOH), desilyla-
tion (CsF), deprotection of the carboxylic acid group
([Pd(PPh3)4]/nBu3SnH[13]), and Cbz cleavage (10% Pd/C,
NH4HCO2) via intermediate 26. It is important to note that
the four-step deprotection sequence is carried out without
work-ups and requires only two purifications (at the stages
where 26 and 1 are formed). An interesting solvent effect was
observed during the course of studying the desilylation of this
series of compounds. Namely, it was found that the phenolic
silyl groups could be cleanly removed without affecting the
other secondary silyl-protected hydroxyl groups on the core of
vancomycin by carrying out the CsF-induced deprotection in
CH3CN rather than DMF.
In conclusion, we have prepared a new set of selenium-
based safety-catch linkers for carboxylic acids, alcohols, and
amines. The utility of one of these linkers was demonstrated
with a solid-phase semisynthesis of vancomycin (1). The
developed technology and sequence has potential for the
construction of vancomycin libraries for biological screening
purposes starting from the readily available vancomycin
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scaffold.
Received: September 20, 1999 [Z14037]
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1998, 110, 2677 ± 2680; Angew. Chem. Int. Ed. 1998, 37, 2534 ± 2537;
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[13] The large difference in polarity between nBu3SnH and the reaction
product together with the insolubility of nBu3SnH in the HPLC
solvent system did not warrant the use of the polymer-bound tin
hydride in this instance.
[1] a) Combinatorial Chemistry and Molecular Diversity in Drug Discov-
ery (Eds.: E. M. Gordon, J. F. Kerwin, Jr.), Wiley, New York, 1998,
p. 516; b) R. E. Dolle, Mol. Diversity 1998, 3, 199 ± 233; c) R. E. Dolle,
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4946.
1088
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Angew. Chem. Int. Ed. 2000, 39, No. 6